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The induction of cell death by the combination treatment with statin, lipid and derivative of steroid

他汀类药物、脂质及类固醇衍生物联合治疗诱导细胞死亡

基本信息

批准号：
16590131
负责人：
IWAKAWA Seigo
金额：
$ 1.98万
依托单位：
Kobe Pharmaceutical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

项目摘要

We examined the combined effect of statin, lipid and a steroid derivative on the induction of cellular death in human cancer cells.We prepared oil-in-water (O/W) lipid emulsions and studied the disposition of the emulsions. The results of the disposition study indicated that the O/W lipid emulsions prepared with n-3 polyunsaturated fatty acid-enriched triglyceride (TG) and egg-yolk lecithin were useful as drug carriers for lipophilic drugs and that O/W lipid emulsions prepared with soy oil and egg-yolk lecithin were also useful.The effect of O/W emulsions containing n-3 polyunsaturated fatty acid-enriched TG on the survival of human breast carcinoma (MCF-7) was studied. The O/W emulsions containing eicosapentaenoic acid (EPA)-enriched TG inhibited cell growth in MCF-7. The effect of the O/W emulsions containing EPA-enriched TG was not attributable to the uptake quantity of O/W emulsions. Intracellular lipid peroxidation was suggested to contribute to the cancer cell death.Next, we exam … More ined the cytotoxicity in human renal carcinoma (ACHN and ACVB) by depletion of glutathione with buthionine sulfoximine (BSO) treatment under 40% O_2. After exposure to 40% O_2, the extent of cell death was increased, compared with that under 20% O_2. We observed that treatment with 2-methoxyestradiol (2-ME), an metabolite of 17β-estradiol, under 40% O_2 showed an enhanced growth inhibition activity for ACHN and ACVB and that the combination with 2-ME and hydrogen peroxide or indometacin under 40% O_2 resulted in an increase in the intracellular reactive oxygen species (ROS) levels and showed an enhanced growth inhibition activity.ACVB was sensitive to simvastatin compared with pravastatin for cell survival. We observed that cytotoxicity for ACVB by simvastatin was attributable to the depletion of mevalonate and geranylgeranylpyrophosphate. The inhibitory activity of docosahexaenoic acid on the survival for ACVB was suggested to be due to the combined effects of both increased intracellular H_2O_2 levels and decreased intracellular farnesylpyrophosphate and geranylgeranylpyrophosphate levels.This study demonstrated significant combination effects of statin, lipid and derivative of steroid on the cellular death of cancer cells. Less

我们研究了他汀类药物、脂质和一种类固醇衍生物在诱导人癌细胞死亡方面的联合作用。我们制备了水包油(O/W)脂肪乳剂，并研究了乳剂的处置。药物处置研究结果表明，富含n-3多不饱和脂肪酸的甘油三酯和蛋黄卵磷脂制备的O/W脂肪乳剂可作为亲脂性药物的药物载体，大豆油和蛋黄卵磷脂制备的O/W脂肪乳剂也可作为亲脂性药物的载体。含有二十碳五烯酸(EPA)富含TG的O/W乳剂抑制MCF-7细胞生长。富含EPA的Tg的O/W乳状液的效果与O/W乳状液的摄取量无关。细胞内的脂质过氧化被认为是癌细胞死亡的原因。接下来，我们检测…进一步研究了在40%O_2条件下，谷胱甘肽联合丁硫氨酸亚磺胺对人肾癌细胞的毒性作用。与20%O_2相比，40%O_2处理后，细胞死亡程度增加。我们观察了17β-雌二醇的代谢产物2-甲氧基雌二醇(2-ME)对人肾癌细胞的作用。在40%O2条件下，对ACHN和ACVB的生长抑制活性增强，在40%O2条件下，2-ME与过氧化氢或吲哚美辛联合使用，细胞内ROS水平升高，细胞生长抑制活性增强。ACVB对辛伐他汀较普伐他汀敏感。我们观察到辛伐他汀对ACVB的细胞毒性可归因于甲氧戊酸和香叶基焦磷酸的耗竭。二十二碳六烯酸对ACVB细胞存活的抑制作用可能是由于细胞内H_2O_2水平的升高和细胞内法尼基焦磷酸和香叶基焦磷酸水平的降低所致。本研究证实了他汀类、脂质和类固醇衍生物对癌细胞死亡的显著联合作用。较少